Implantation of electrodes for electrical deep brain stimulation (DBS) and deep brain recording of neuronal signals are widely used for treatment of brain malfunctions. High frequency electrical DBS is used in cases such as Parkinson's disease (PD), epilepsy, major depression, dystonia and essential tremor. For this, electrodes are implanted in deep brain sites such as the subthalamic nucleus (STN), globus pallidus (GPi) and the pedunculopontine nucleus. Once the electrodes are surgically positioned, no changes can be carried out in their position. Despite the broad research and clinical use, no optimal architecture and placement of the stimulating electrodes was found. It appears that for each individual, the architecture and placement should be optimized separately. For this reason, the number of electrodes and their spatial distribution are critical for the success of the treatment. Additionally, in order to position the electrodes, growing number of surgeons use both magnetic resonance imaging (MRI) and online recordings of the neuronal activity. Such recording is fundamental for positioning the stimulating electrodes, and allow high online spatial resolution during the insertion of the electrode without the dependency in MRI.
Recording of the brain's neuronal activity is also used to interface with peripheral prosthesis as a means for functional rehabilitation of individuals with motor disabilities, to control wheel chairs (Wolpaw and McFarland, 2004), guide computerr cursors (Santhanam et al., 2008) and robotic arms (Abbott, 2006). Multi-electrode arrays (MEAs) are presently used for recording of multichannel neuronal signals mostly from cortical areas of the brain (House et al., 2006; Nicolelis, 2003). A constraining factor of these rehabilitation attempts is the ability to readout a stable and reliable neuronal data. Therefore, the electrode-brain interface needs to withstand the challenge of chronic recording and high signal to noise ratio with minimal effect on the surrounding tissue.
Previous studies reported a decrease in the quality of neuronal signals and the number of functional electrodes in chronic multi-electrode arrays (MEAs) recordings (Polikov et al., 2005). Follow-up studies reported a reduction in the DBS-dependent improvement in motor control in PD patients over time (Wider et al., 2008). Reduced efficacy over time of both recording and stimulation procedures were associated with the brain's immune response, i.e., a glial scar formation, to the chronically implanted electrodes (Nicolelis, 2003; McConnell et al., 2009, Hughes et al., 2011). The glial scar encapsulates the electrode creating a physical barrier between the electrode and the neurons (Polikov et al., 2005; Tate, 2001), and thus, defines a time limit for chronic neuronal recording and stimulation due to the formation of a glial-scar. The current strategy to overcome this problem of biocompatibility of electrode-brain interface is redundancy, thus using a large number, in the range of hundreds, of electrodes, in order to overcome the glial time limit (Nordhausen et al., 1996; Turner et al., 2008). However, while this strategy may be effective for cortical recordings, it is not applicable for deeper brain sites due to the extensive damage it will cause.
Electrode implantation initiates an immune cascade and secretion of immune response regulation factors such as monocyte chemotactic protein-1 (MCP-1) (Babcock et al., 2003), and pro-inflammatory cytokines such as interleukin-1 (IL-1) (Giulian et al., 1994a; 1994b), interleukin-6 (IL-6) (Woodroofe et al., 1991), and tumor necrosis factor (TNF) (Sheng et al., 1995; Chabot et al., 1997) that through a positive feedback loop support the creation of the glial scar (Eng and Ghirnikar, 1994). Histological analysis of the immune response indicated no significant difference in the amount of glial-scarring to different sizes, their surface physical characteristics or the electrode insertion techniques (Polikov et al., 2005; Polikov et al., 2006). Systemic injection of immune suppressors reduced the glial-scar response (Spataro et al., 2005), yet, resulted in severe peripheral metabolic side effects (Kim and Martin, 2006). Several coating agents were tested in order to reduce the level of glial scarring, including alginate hydrogel matrices embedded with dexamethasone (DEX) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Kim and Martin, 2006). This study showed no increase in the impedance of chronic DEX-coated electrodes, while the impedance of the control electrodes increased by three times within two weeks from implantation, presumably due to the glial scar around the control electrodes. Yet, no electrophysiological or histological data were presented to confirm that the improved impedance stability correlates with improved electrode functionality and biocompatibility. In an additional study, laminin-coated silicon (Si) electrodes were implanted in the rat cortex and brains were examined after one and four weeks for glial scarring (He et al., 2006). Although no difference was found one week after implantation, glial fibrillary acidic protein (GFAP) staining done four weeks after implantation was lower around the laminin-coated electrodes compared to the non-coated control electrodes. This “rescue” effect occurred because the laminin coating passively “camouflaged” the electrode from being identified by the immune system and thus provoked a weaker immune response, indicating that systemic administration of anti-inflammatory agents and electrode protein coatings may serve to minimize glial scarring.
Interleukins (ILs) are cytokines that are known to be scar inducers. In response to brain injury, local inflammatory cells (macrophages) secrete several cytokines, including IL-1, which play a crucial role in the mammalian inflammatory response associated with a wide range of immunologic, metabolic, physiological and hematopoietic activities (Giulian and Tapscott, 1988). The IL-1 family includes three structurally related cytokines, more particularly IL-1α, IL-1β and IL-1 receptor antagonist (IL-1ra), of which IL-1α and IL-1β are pro-inflammatory agonists while IL-1ra blocks IL-1α and IL-1β activity (Morgan et al., 2004; Thompson et al., 1992). All known functions of IL-1 family are mediated via the IL-1 receptor. Systemic administration of IL-1ra was found to effectively inhibit glial-scar development at injury sites (Bendele et al., 2000; Born et al., 2000).
US 2005/0149157 discloses, inter alia, a medical device for various therapeutic indications, said device comprising an electrical device such as an electrode and an anti-scarring agent selected from various categories of agents, e.g., cell cycle inhibitors, wherein the anti-scarring agent inhibits scarring between the device and the host into which the device is implanted. The anti-scarring agent may either coat the device or, alternatively, locally administered to the implantation site.